Interplay of tumor microenvironment and MUC4 in pancreatic cancer. Clinically, MUC4 mucin is aberrantly overexpressed in pancreatic cancer (PC) tissues and its expression is associated with poor prognosis (1). Studies from our laboratory have conclusively established that MUC4 is involved in enhanced motility, invasiveness and drug resistance of tumor cells in vitro and promotes tumorigenicity and metastasis in vivo (2). MUC4 upregulation is one of the early events in pancreatic cancer as indicated by its upregulation in precursor lesions (3). Our previous studies have demonstrated that MUC4 expression in pancreatic cancer cells in part is regulated by cytokines like IFN- y which are potentially secreted by cells of tumor/inflamed pancreas microenvironment. Inflammation is regarded as a precursor to cancer and in case of pancreatic cancer the increasing evidence supporting the association of pancreatitis to pancreatic cancer risk/development underscores the importance of inflammation in this lethal malignancy. It is thus not surprising that like high MUC4 levels, high levels of pro-inflammatory cytokines (IL-1 & IL-12) in tumor correlates with poor prognosis (4). Given the importance of inflammation and involvement of MUC4 in pancreatic cancer development, and regulation of MUC4 by inflammatory cytokines like IFN- y, the overall objective of this proposal is to understand the modulation of MUC4 expression by tumor microenvironment Another aspect of MUC4 and tumor microenvironment is the ability of MUC4 to interact with and possibly modulate the components of extracellular matrix via the unique domain (NIDO). However, to keep the proposal focused and avoid overlap with our ongoing studies the emphasis of the current application is on the regulation of MUC4 by tumor microenvironment (TME).